Our overall objective is to investigate how stress, and by definition an activated hypothalamic-pituitary-adrenal axis (HPA), acts to modify normal function of the hypothalamic- pituitary-gonadal axis (HPG) and to interfere with the normal menstrual cycle in a relevant non-human primate. In the previous funding period, we developed two distinct short-term stress models (inflammatory and psychogenic) in the rhesus monkey and demonstrated that they reliably interfere with normal cyclic function and induce cycle stage- and stress-specific damage that may include a delay in folliculogenesis, a decrease in luteal secretory capability reminiscent of the inadequate luteal phase syndrome, and/or interference with the normal tonic gonadotropin profile. The first two aims will investigate the role of the 2 main HPA neuropeptides, CRH and vasopressin (VP), in the process by which stress interferes with the menstrual cycle by correlating their central release and the effects of specific CRH and VP antagonists to neutralize endogenous HPA activity. Since different stress may activate varying central pathways, which may, in turn, have different sensitivities to ovarian steroids, we will compare HPA and HPG effects in the 2 different stress models and in the follicular and luteal phase of the cycle. The goal of aim 3 is to develop a long-term stress that results in amenorrhea, the defining symptom of the established clinical functional hypothalamic chronic anovulation syndrome. Here, we will test whether two unrelated stimuli, such as a psychogenic stress and diet, can synergize to produce the syndrome and investigate the role of CRH, VP and opioid peptides in established amenorrhea. We will also investigate whether leptin, in a new role as a modulator of stress-related endocrine function and reproduction, plays a protective role against amenorrhea. Overall, the data will contribute to our understanding of the varying mechanisms whereby different stress stimuli interfere with reproductive function and of how the ovarian endocrine milieu influences this process. They will provide novel information on the early stages whereby a stress, insufficient to interrupt the cycle, interferes with normal cyclic function and may result in infertility, and open new avenues of treatment in the chronic anovulation syndrome.